Serum withdrawal-induced post-transcriptional stabilization of cyclooxygenase-2 mRNA in MDA-MB-231 mammary carcinoma cells requires the activity of the p38 stress-activated protein kinase

Overexpression of the cyclooxygenase-2 (COX-2) gene is observed in several neoplastic diseases. However, molecular mechanisms involved in the regulati on of expression of COX-2 are not well understood. In this report, we descr ibe a unique post-transcriptional regulatory mechanism of COX-2 mRNA stabil ization in MDA-MB-231 cells, a highly metastatic cell line derived from a h uman mammary tumor. High levels of COX-2 mRNA, protein, and enzyme activity were induced by serum withdrawal, which were potently inhibited by the add ition of serum or >100-kDa serum factor. Nuclear run-on analysis and actino mycin D chase experiments indicate that regulation is primarily at the leve l of post-transcriptional mRNA stability. Interestingly, SB203580, an inhib itor of the p38 stress-activated protein kinase (SAPK), and overexpression of the dominant-negative p38 alpha construct potently inhibited the serum w ithdrawal-induced COX-2 mRNA levels. Indeed, the half-life of COX-2 mRNA de creased from 9 to 4.5 h after SB203580 treatment, suggesting that signal tr ansduction by the p38 SAPK pathway is required for COX-2 mRNA stability.